Novartis Pharmaceuticals UK Ltd

The recommended dose of Glivec is 400 mg/day for the adjuvant treatment of adult patients following resection of GIST. Optimal treatment duration is not yet established. Length of treatment in the clinical trial supporting this indication was 3612 months (see section 5.1).

The following text has been added to Section 5.1 following Table 7:

A second multicentre, open label phase III study (SSG XVIII/AIO) compared 400 mg/day Glivec 12 months treatment vs. 36 months treatment in patients after surgical resection of GIST and one of the following: tumour diameter > 5 cm and mitotic count > 5/50 high power fields (HPF); or tumour diameter > 10 cm and any mitotic count or tumour of any size with mitotic count > 10/50 HPF or tumours ruptured into the peritoneal cavity. There were a total of 397 patients consented and randomised to the study (199 patients on 12-month arm and 198 patients on 36-month arm), median age was 61 years (range 22 to 84 years). The median time of follow-up was 54 months (from date of randomisation to data cut-off), with a total of 83 months between the first patient randomised and the cut-off date.

The primary endpoint of the study was recurrence-free survival (RFS), defined as the time from date of randomisation to the date of recurrence or death from any cause.

Thirty-six (36) months of Glivec treatment significantly prolonged RFS compared to 12 months of Glivec treatment (with overall Hazard Ratio (HR) = 0.46 [0.32, 0.65], p<0.0001) (Table 8, Figure 1).

In addition, thirty-six (36) months of Glivec treatment significantly prolonged overall survival (OS) compared to 12 months of Glivec treatment (HR = 0.45 [0.22, 0.89], p=0.0187) (Table 8, Figure 2).

Longer duration of the treatment (> 36 months) may delay the onset of further recurrences; however the impact of this finding on the overall survival remains unknown.

The total number of deaths were 25 for the 12-month treatment arm and 12 for the 36-month treatment arm.

Treatment with imatinib for 36 months was superior to treatment for 12 months in the ITT analysis, i.e. including the entire study population. In a planned subgroup analysis by mutation type, the HR for RFS for 36 months of treatment for patients with mutations of exon 11 was 0.35 [95% CI: 0.22, 0.56]. No conclusions can be drawn for other less common mutation subgroups due to the low number of observed events.

Table 8       12-month and 36-month Glivec treatment (SSGXVIII/AIO Trial)

For a the full list of excipients, see section 6.1.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients with cardiac disease

Patients with cardiac disease, or risk factors for cardiac failure or history of renal failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac or renal failure should be evaluated and treated.

Pregnancy

There are no adequatelimited data on the use of imatinib in pregnant women. Studies in animals have however shown reproductive toxicity (see section 5.3) and the potential risk for the foetus is unknown. Glivec should not be used during pregnancy unless clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus.

Women of childbearing potential must be advised to use effective contraception during treatment.

Breast-feeding

There is limited information on imatinib distribution on human milk. Studies in two breast-feeding women revealed that both imatinib and its active metabolite can be distributed into human milk. The milk plasma ratio studied in a single patient was determined to be 0.5 for imatinib and 0.9 for the metabolite, suggesting greater distribution of the metabolite into the milk. Considering the combined concentration of imatinib and the metabolite and the maximum daily milk intake by infants, the total exposure would be expected to be low (~10% of a therapeutic dose). However, since the effects of low-dose exposure of the infant to imatinib are unknown, women taking imatinib should not breast-feed.

Fertility

In non-clinical studies, the fertility of male and female rats was not affected (see section 5.3). Studies on patients receiving Glivec and its effect on fertility and gametogenesis have not been performed. Patients concerned about their fertility on Glivec treatment should consult with their physician.

No studies on the effects on the ability to drive and use machines have been performed. However, pPatients should be advised that they may experience undesirable effects such as dizziness, or blurred vision or somnolence during treatment with imatinib. Therefore, caution should be recommended when driving a car or operating machinery.

Date of first authorisation: 1107.11 November.2003 2001

Date of first latest renewal: 07 November .11.2006

In section 4.2 reference is made throughout to "adult" patients instead of patients.  A new heading "Special populations" has been added above Paediatric use.  The paragraph on Renal insufficiency has been changed as shown below:

Renal insufficiency: Since the renal clearance of imatinib is negligible, a decrease in free imatinib clearance is not expected in patients with renal insufficiency. Patients with mild or moderate renal dysfunction or on dialysis (creatinine clearance = 20–59 ml/min) should be given the minimum recommended dose of 400 mg daily as starting dose. Although very limited information is available, patients with severe renal dysfunction (creatinine clearance = < 20 ml/min) or on dialysis could also start at the same dose of 400 mg. However, in these patients caution is recommended. The dose can be reduced if not tolerated., or If tolerated, the dose can be increased for lack of efficacy (see sections 4.4 and 5.2).

In section 4.4 the following paragraph has been amended:

When Glivec is co-administered with other medicinal products, there is a potential for drug interactions (see section 4.5). Caution should be used when taking Glivec with ketoconazole or other strong CYP3A4 inhibitors, CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporin or pimozide) or CYP2C9 substrates with a narrow therapeutic window (e.g. warfarin and other coumarin derivatives) (see section 4.5).

In Section 4.5 a deletion has been made as shown below.

Active substances that may decrease imatinib plasma concentrations:

Substances that are inducers of CYP3A4 activity could increase metabolism and decrease imatinib plasma concentrations. Co-medications which induce CYP3A4 (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, fosphenytoin, primidone or Hypericum perforatum, also known as St. John’s Wort) may significantly reduce exposure to Glivec, potentially increasing the risk of therapeutic failure. Pretreatment with multiple doses of rifampicin 600 mg followed by a single 400 mg dose of Glivec resulted in decrease in C_max and AUC_(0-∞) by at least 54% and 74%, of the respective values without rifampicin treatment. Similar results were observed in patients with malignant gliomas treated with Glivec while taking enzyme-inducing anti-epileptic drugs (EIAEDs) such as carbamazepine, oxcarbazepine and phenytoin. The plasma AUC for imatinib decreased by 73% compared to patients not on EIAEDs. Concomitant use of rifampicin or other strong CYP3A4 inducers and imatinib should be avoided.

In section 5.1 an additional paragraph has been inserted at the front of the section under the first line as follows and a new heading added to the next paragraph:

Mechanism of action

Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor (SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and beta (PDGFR-alpha and PDGFR-beta). Imatinib can also inhibit cellular events mediated by activation of these receptor kinases.

Pharmacodynamic effects

Imatinib is a protein-tyrosine kinase inhibitor which potently inhibits the Bcr-Abl tyrosine kinase at the in vitro, cellular and in vivo levels. The compound selectively inhibits proliferation and induces apoptosis in Bcr-Abl positive cell lines as well as fresh leukaemic cells from Philadelphia chromosome positive CML and acute lymphoblastic leukaemia (ALL) patients.

In vitro, Glivec inhibits paracetamol O-glucuronidation with (Ki value of 58.5 micromol/l at therapeutic levels). This inhibition has not been observed in vivo after the administration of Glivec 400 mg and paracetamol 1000 mg. Higher doses of Glivec and paracetamol have not been studied.

Caution should therefore be exercised when using high doses of Glivec and paracetamol concomitantly, especially with high doses of paracetamol.

 
Continues as present...

Section 5.1

Minor change made before Table 7:

The risk of recurrence in patients after surgery of their primary GIST was retrospectively assessed based on the following prognostic factors: tumour size, mitotic index, tumour location. Mitotic index data were available for 556 of the 7173 intention-to-treat (ITT) population. The results of subgroup analyses according to the United States National Institutes of Health (NIH) and the Armed Forces Institute of Pathology (AFIP) risk classifications are shown in Table 7. No benefit was observed in the low and very low risk groups. No overall survival benefit has been observed.

Children and adolescents
There have been case reports of growth retardation occurring in children and pre-adolescents receiving imatinib. The long-term effects of prolonged treatment with imatinib on growth in children are unknown. Therefore, close monitoring of growth in children under imatinib treatment is recommended (see section 4.8).

In Section 4.8, Undesirable effects, Table 1 and 2 listing adverse events have been updated and now read as follows:

Adverse reactions

Adverse reactions reported as more than an isolated case are listed below, by system organ class and by frequency. Frequency categories are defined using the following convention: very common (=1/10), common (=1/100 to <1/10), uncommon (=1/1,000 to <1/100), rare (=1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of frequency, the most frequent first.

Adverse reactions and their frequencies reported in Table 1 are based on the main registration studies.

Table 1 Adverse reactions in clinical studies

1          Pneumonia was reported most commonly in patients with transformed CML and in patients with GIST.

2          Headache was the most common in GIST patients.

3          On a patient-year basis, cardiac events including congestive heart failure were more commonly observed in patients with transformed CML than in patients with chronic CML.

4          Flushing was most common in GIST patients and bleeding (haematoma, haemorrhage) was most common in patients with GIST and with transformed CML (CML-AP and CML-BC).

5          Pleural effusion was reported more commonly in patients with GIST and in patients with transformed CML (CML-AP and CML-BC) than in patients with chronic CML.

6+7      Abdominal pain and gastrointestinal haemorrhage were most commonly observed in GIST patients.

8          Some fatal cases of hepatic failure and of hepatic necrosis have been reported.

9          Musculoskeletal pain and related events were more commonly observed in patients with CML than in GIST patients.

The following types of reactions have been reported mainly from post-marketing experience with Glivec. This includes spontaneous case reports as well as serious adverse events from ongoing studies, the expanded access programmes, clinical pharmacology studies and exploratory studies in unapproved indications. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to imatinib exposure.

Table 2 Adverse reactions from post-marketing reports

In section 5.1 Pharmacodynamic properties, the following paragraph has been added to the information on clinical studies in chronic myeloid leukaemia

The European Medicines Agency has waived the obligation to submit the results of studies with Glivec in all subsets of the paediatric population in Philadelphia chromosome (bcr-abl translocation)-positive chronic myeloid leukaemia (see section 4.2 for information on paediatric use).

In section  section 4.9 and 7 there have been a few minor editorial changes that have  been made.

In section 4.1, Therapeutic Indications the following has been added:

the adjuvant treatment of adult patients who are at significant risk of relapse following resection of Kit (CD117)-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment

In section 4.2  Posology and Method of Administration,  the following has been added under Posology for GIST

The recommended dose of Glivec is 400 mg/day for the adjuvant treatment of adult patients following resection of GIST. Optimal treatment duration is not yet established. Length of treatment in the clinical trial supporting this indication was 12 months.

In section 4.6, Pregnancy and Lactation now reads as follows:

Lactation

There is limited information on imatinib distribution on human milk. Studies in two breast-feeding women revealed that both imatinib and its active metabolite can be distributed into human milk. The milk plasma ratio studied in a single patient was determined to be 0.5 for imatinib and 0.9 for the metabolite, suggesting greater distribution of the metabolite into the milk. Considering the combined concentration of imatinib and the metabolite and the maximum daily milk intake by infants, the total exposure would be expected to be low (~10% of a therapeutic dose). However, since the effects of low-dose exposure of the infant to imatinib are unknown, women taking imatinib should not breast-feed.

In section 4.8, Undesirable effects, the following has been added to Table 1:

Section 4.9, Overdose now reads as follows:

Experience with doses higher than the recommended therapeutic dose is limited. Isolated cases of Glivec overdose have been reported spontaneously and in the literature. In the event of overdose the patient should be observed and appropriate symptomatic treatment given. Generally the reported outcome in these cases was “improved” or “recovered”. Events that have been reported at different dose ranges are as follows:

Adult overdose:

1200 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.

1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine phosphokinase, increased bilirubin, gastrointestinal pain.

6400 mg (single dose): One case reported in the literature of one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, increased transaminases.

8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.

Paediatric overdose:

One 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia and another 3-year-old male exposed to a single dose of 980 mg dose experienced decreased white blood cell count and diarrhoea.

Section 5.1 Pharmacodynamic properties now states the following:

Clinical study in adjuvant GIST

In the adjuvant setting, Glivec was investigated in a multicentre, double-blind, long-term, placebo-controlled phase III study (Z9001) involving 773 patients. The ages of these patients ranged from 18 to 91 years. Patients were included who had a histological diagnosis of primary GIST expressing Kit protein by immunochemistry and a tumour size ≥ 3 cm in maximum dimension, with complete gross resection of primary GIST within 14‑70 days prior to registration. After resection of primary GIST, patients were randomised to one of the two arms: Glivec at 400 mg/day or matching placebo for one year.

The primary endpoint of the study was recurrence-free survival (RFS), defined as the time from date of randomisation to the date of recurrence or death from any cause.

Glivec significantly prolonged RFS, with 75% of patients being recurrence-free at 38 months in the Glivec group vs. 20 months in the placebo group (95% CIs, [30 - non-estimable]; [14 - non-estimable], respectively); (hazard ratio = 0.398 [0.259‑0.610], p<0.0001). At one year the overall RFS was significantly better for Glivec (97.7%) vs. placebo (82.3%), (p<0.0001). The risk of recurrence was thus reduced by approximately 89% as compared with placebo (hazard ratio = 0.113 [0.049‑0.264]).

The risk of recurrence in patients after surgery of their primary GIST was retrospectively assessed based on the following prognostic factors: tumour size, mitotic index, tumour location. Mitotic index data were available for 556 of the 773 intention-to-treat (ITT) population. The results of subgroup analyses according to the United States National Institutes of Health (NIH) and the Armed Forces Institute of Pathology (AFIP) risk classifications are shown in Table 7. No benefit was observed in the low and very low risk groups. No overall survival benefit has been observed.

Table 7            Summary of Z9001 trial RFS analyses by NIH and AFIP risk

* Full follow-up period; NE – Not estimable

Section 10, Date of Revision of the Text now reads 29 April 2009

• New indication - Ph+ acute lymphoblastic leukaemia & unresectable dermatofibrocarcoma protuberans (DFSP)
• Update to paedicatric labelling for chronic myeliod leukaemia (CML)

• Dose adjustments for neutropenia and thrombocytopenia - table reformatted

• Paragraph on concomitant high dose chemo in Ph+ ALL patients added

• Paragraph on concomitant high dose chemo in Ph+ ALL patients added

 SECTION 4.7:

•  Reworded slightly

• Neoplasms added to table
• Paragraph on liver toxicity with high dose chemo in Ph+ ALL patients added
• In Lab findings - sentance on paediatric use in CML patients added

• Info on paedicatric use, use in Ph+ ALL and use in DFSP added
• Table 3 added

•  Macrogel, Talc & Hypromellose added